The importance of genetics in alcoholism is well established but the neurobiological mechanisms underlying predisposition are poorly understood and are likely to be multi-factorial. In our studies in alcoholics we have documented reductions in striatal DA D2 receptors (D2-R) and in metabolic activity in orbitofrontal cortex (OFC). Since these abnormalities persisted with detoxification we questioned whether they reflected predisposing factors for alcoholism. Pilot studies in subjects at high risk for alcoholism (HR) (positive family history for alcoholism) revealed decreases in OFC activity but increases in D2-R. These results coupled with our findings that increasing D2-R reduces alcohol intake in rats and the fact that after all the HR subjects were not alcoholics even though they had a family history for alcoholism led us to hypothesize that while decreased OFC may be a predisposing factor elevated D2-R may be protective. Here we propose to test these hypotheses, which are based on the postulate that predisposition for alcoholism reflects the balance between vulnerability and protective factors. Specific hypotheses are as follows: [unreadable] (1) A vulnerability factor in HR subjects is decreased OFC activity since this region is implicated in the lack of control and compulsive drug consumption characteristic of addictions including alcoholism, (2) A protective factor in HR subjects is high D2-R, which we postulate protects them against alcoholism by regulating the response of brain reward circuits to alcohol intoxication, (3) HR subjects will have reduced behavioral and regional brain metabolic responses to alcohol intoxication when compared with subjects at low risk for alcoholism (LR) (negative family history of alcoholism). Alcohol induced metabolic and behavioral effects will be modulated by D2-R levels and activity in OFC. [unreadable] To test these hypotheses we will use PET to measure D2-R availability using [11C] raclopride and to measure regional brain glucose metabolism using 18FDG at baseline and during alcohol intoxication (0.75 g/kg) in 60 HR and 60 LR subjects. To increase the probability of recruiting subjects with a high likelihood of having inherited the predisposition for alcoholism subjects will be pre-selected by their P300, which serves as an endophenotypic marker for vulnerability (HR subjects will have low P300 amplitudes and LR normal P300). [unreadable] A better understanding of the neurobiological mechanisms underlying protective and predisposing factors in alcoholism would allow development of better preventive interventions and may help in the design of corrective therapeutic strategies [unreadable] [unreadable]